Pharmaceutical formulation and process

ABSTRACT

A new oral pharmaceutical dosage form comprising a core material that contains a proton pump inhibitor, one or more alkaline reacting compounds and optionally pharmaceutical excipients having a water soluble separating layer and an enteric coating layer. The core material as such is alkaline reacting and the separating layer between the alkaline reacting core material and the enteric coating layer is formed in situ as a water soluble salt between the alkaline reacting compound(s) and the enteric coating polymer. The invention also describes a new efficient process for the manufacture of such a dosage form comprising two functionally different layers in one manufacturing step, and its use in medicine.

FIELD OF THE INVENTION

[0001] The present invention refers to new pharmaceutical formulationscomprising acid labile heterocyclic compounds with gastric inhibitoryeffect, in the following referred to as proton pump inhibitors. The newformulations are intended for oral use. Furthermore, the presentinvention refers to a new method for the manufacture of such aformulation and, the use of the new formulations in medicine.

BACKGROUND OF THE INVENTION

[0002] The proton pump inhibitors are for example compounds of thegeneral formula I

[0003] wherein

[0004] N in the benzimidazole moiety means that one of the carbon atomssubstituted by R₆-R₉ optionally may be exchanged for a nitrogen atomwithout any substituents;

[0005] R₁, R₂ and R₃ are the same or different and selected fromhydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio,alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl andphenylalkoxy;

[0006] R₄ and R₅ are the same or different and selected from hydrogen,alkyl and aralkyl;

[0007] R′₆ is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;

[0008] R₆-R₉ are the same or different and selected from hydrogen, alkylalkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyltrifluoroalkyl, or adjacent groups R₆-R₉ form ring structures which maybe further substituted;

[0009] R₁₀ is hydrogen or forms an alkylene chain together with R₃ and

[0010] R₁₁ and R₁₂ are the same or different and selected from hydrogen,halogen or alkyl and alkyl groups, alkoxy groups and moities thereof maybe branched and straight C₁-C₉-chains or comprise cyclic alkyl groups,for example cycloalkylalkyl.

[0011] Examples of proton pump inhibitors according to formula I are

[0012] The proton pump inhibitors used in the dosage forms of theinvention may be used in neutral form or in the form of an alkalinesalt, such as for instance the Mg²⁺, C²⁺, Na⁺, K⁺ or Li⁺ salts,preferably the Mg²⁺ salts. Further where applicable, the compoundslisted above may be used in racemic form or in the form of asubstantially pure enantiomer thereof, or alkaline salts of theracemates or the single enantiomers.

[0013] Suitable proton pump inhibitors are for example disclosed inEP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 andWO90/06925, WO91/19711, WO91/19712, and further especially suitablecompounds are described in WO94/27988 and WO95/01977.

[0014] These proton pump inhibitors are, as already mentioned, usefulfor inhibiting gastric acid secretion in mammals and man. In a moregeneral sense, they may be used for prevention and treatment ofgastric-acid related diseases in mammals and man, including e.g. refluxesophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer.Furthermore, they may be used for treatment of other gastrointestinaldisorders where gastric acid inhibitory effect is desirable e.g. inpatients on NSAID therapy, in patients with Non Ulcer Dyspepsia, inpatients with symptomatic gastro-esophageal reflux disease, and inpatients with gastrinomas. They may also be used in patients inintensive care situations, in patients with acute upper gastrointestinalbleeding, pre- and postoperatively to prevent aspiration of gastric acidand to prevent and treat stress ulceration. Further, they may be usefulin the treatment of Helicobacter infections and diseases related tothese.

[0015] These proton pump inhibitors are, however, susceptible todegradation/transformation in acidic reacting and neutral media. Thedegradation is catalyzed by acidic reacting compounds and the protonpump inhibitors are usually stabilized in mixtures with alkalinereacting compounds.

[0016] In respect to the stability properties of the proton pumpinhibitors mentioned above, it is obvious that a proton pump inhibitorin an oral solid dosage form must be protected from contact with theacidic reacting gastric juice and the active substance must betransferred in intact form to that part of the gastrointestinal tractwhere pH is less acidic, neutral or alkaline and where rapid absorptionof the pharmaceutically active substance, i.e. the proton pumpinhibitor, can occur.

[0017] A pharmaceutical dosage form of these proton pump inhibitors isbest protected from contact with acidic gastric juice by an entericcoating layer. In U.S. Pat. No. 4,853,230 such enteric coatedpreparations of different acid labile substances are described. Saidpreparations contain an alkaline core material comprising the activesubstance, a separating layer and an enteric coating layer.

[0018] Ordinary enteric coating layers, however, comprise compoundswhich contain acidic groups. If covered with such an enteric coatinglayer, the acid labile substance may rapidly decompose by direct orindirect contact with the acidic groups resulting in discoloration ofthe content and loss in content of the active compound with the passageof time. The discoloration can be avoided by applying some type ofseparating layer between the core material comprising the susceptibleproton pump inhibitor and the enteric coating layer.

[0019] Thus, there are a lot of patent applications describing such aseparating layer between a core material comprising the pharmaceuticallyactive substance and an enteric coating layer. See for instance, U.S.Pat. No. 4,786,505, EP 0,277,741 and EP 0,342,522. The prior arttechniques to apply at least two different layers on a pellet core or atablet comprising an acid labile compound is rather complicated andthere is a demand for finding new processes and formulations to simplifythe manufacturing of such enteric coated articles comprising acid labilesubstances.

SUMMARY OF THE INVENTION

[0020] According to one aspect of the invention a new pharmaceuticaldosage form is provided in the form of an enteric coated tablet.Alternatively, individually enteric coated units are prepared and filledinto a capsule, a sachet or included in a tableted multiple unit dosageform.

[0021] The present invention is characterized by the presence of aseparating layer between an alkaline reacting core material comprising apharmaceutically active acid labile substance and an enteric coatinglayer, wherein the separating layer comprises a water soluble salt of anenteric coating polymer.

[0022] According to a second aspect the present invention provides aprocess for the manufacture of two functionally different layers in onemanufacturing step. By such a process a separating layer comprising awater soluble salt of an enteric coating polymer is obtained, as well asthe enteric coating layer itself.

[0023] Thus, the present invention simplifies the preparation of entericcoated articles comprising a separating layer between a core materialand an enteric coating layer by providing a new process for themanufacture of such dosage forms. According to said process theseparating layer is formed by an in situ reaction between the entericcoating polymer and the alkaline core material comprising thepharmaceutically active substance.

BRIEF DESCRIPTION OF THE FIGURES

[0024]FIG. 1 is a photo showing a cross-section of a tablet manufacturedaccording to the invention described in the present specification.

[0025]FIG. 2 is a schematic drawing of the photo disclosed in FIG. 1.The tablet has an enteric coating layer (3), which has been applied onan alkaline core material (1) comprising the pharmaceutically activesubstance. Between the enteric coating layer (3) and the core material(1) there is a separating layer (2) shown. The separating layer (2) ison the photo inked by a fluorescent colour.

DETAILED DESCRIPTION OF THE INVENTION

[0026] One object of the present invention is to provide a new entericcoated pharmaceutical formulation comprising a core material thatcontains a proton pump inhibitor, one or more alkaline reactingcompound(s) and optionally pharmaceutically acceptable excipients, whichformulation has a water soluble separating layer and an enteric coatinglayer and wherein the core material is alkaline and the separating layeris being formed in situ during the enteric coating as a salt between theenteric coating polymer(s) and an alkaline reacting compound(s) in thecore material.

[0027] Another object of the present invention is to provide a newprocess for the manufacture of such enteric coated pharmaceuticalformulations comprising a core material of a proton pump inhibitorwherein a separating layer is formed in situ during the enteric coatingby a reaction between the enteric coating polymer(s) and one or morealkaline reacting compound(s) in the core material, i.e. thereby a saltis formed between the enteric coating polymer(s) and the alkalinereacting compound(s).

[0028] The new pharmaceutical dosage form according to the invention isfurther characterized in the following way. Compacted tablets orindividual cores (in the form of small tablets, small beads, granules orpellets) contain the proton pump inhibitor in the form of a racemate orone of its single enantiomers or an alkaline salt of said compound orone of its single enantiomers. The tablets or individual cores, thatalso comprise one or more alkaline reacting compound(s) which is in theposition to form a water soluble salt by a reaction with an entericcoating material, are coated with one or more enteric coating layers.

[0029] The separating layer is formed in situ by a reaction between theenteric coating polymer(s) and the alkaline reacting compound(s) in thecore material during the enteric coating process.

[0030] The core material for the manufacture of enteric coated pelletscan be prepared according to two main principles. Firstly, seeds can belayered with the proton pump inhibitor, alkaline reating compound(s) andnecessary excipients to give an alkaline reacting core material, or thealkaline reacting core material can be prepared as substantiallyhomogeneous cores or tablets comprising the proton pump inhibitor andthe alkaline reacting compound(s).

[0031] The alkaline reacting compound(s) in the core material or tabletcores, necessary for an in situ reaction with the enteric coatingpolymer, is a substance in the position to form a water soluble saltwith an enteric coating polymer. Such alkaline reacting compounds arefor instance amino acids, such as lysine, arginine, ornitine, histidine,organic buffering compounds such as trometamine (i.e. Tris-buffer),N-amino sugars such as N-methyl-D-glucamine (i.e. Meglumine ),N-ethyl-D-glucamine (i.e. Eglumine ), glucosamine,disodium-N-stearoyl-glutamate, heterocyclic amine derivatives such aspiperazine or its hexahydrate, N-methylpiperazine, morpholine,1-(2-hydroxyethyl)pyrrolidine, alkali salts of citric acid, tartaricacid, caproic acid or fatty acids, alkali metal phosphates, silicates orcarbonates, sodium, potassium, magnesium, calcium or aluminiumhydroxides and organic amines such as ethylamine, dicyclohexyl amine ortriethanolamine, or alkaline ammonium salts.

[0032] The core material as such should be an alkaline reacting corematerial, i.e. the amount of alkaline reacting compound(s) available inthe core material should be enough to form a salt between the entericcoating polymer(s) and the alkaline reacting compound(s).

[0033] Thus, the concentration of alkaline reacting compound(s) in thecore material (before applying the enteric coating polymer) is fromapproximately 0.1 mmol/g dry ingredients in the alkali containing partof the core material up to approximately 15 mmol/g, preferably theconcentration shall be more than 0.3 mmol/g dry ingredients in thealkaline part of the core material.

[0034] The upper limit range is only restricted by the need to include apharmaceutically active ingredient and excipients such as binders etc inthe alkaline core material. The concentration of alkaline reactingcompound(s) may be illustrated as follows. For a core material where,for instance, 10% w/w of a proton pump inhibitor and 5% w/w ofexcipients (binders, surfactants etc) are to be included, 85% w/wremains to possible disposition to the alkaline reacting compound(s).For such a core material, this means that, if the alkaline reactingcompound is sodium bicarbonate which has the rather low molecular weightof 84 u, the concentration of the alkaline material in the core materialwill be [(85/84)/100]×1 000, i.e. approximately 9.9 mmol/g in the alkalicontaining part/layer.

[0035] One or more enteric coating layers are applied onto the preparedcore material or tablets by using a suitable aqueous coating technique.The enteric coating material is dispersed and/or dissolved in an aqueousvehicle. As enteric coating polymer(s) one or more, separately or incombination, of the following can be used; methacrylic acid copolymers,cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylceuulose acetate succinate, polyvinyl acetatephthalate, cellulose acetate trimellitate, carboxymethylethylcellulose,shellac or other suitable enteric coating polymer(s).

[0036] The enteric coating layer(s) may contain pharmaceuticallyacceptable plasticizers to obtain desired mechanical properties, such asflexibility and hardness of the enteric coating layer(s). The amount ofplasticizer is optimized for each enteric coating formulation, inrelation to selected enteric coating polymer(s), selected plasticizer(s)and the applied amount of said polymer(s). The mechanical properties ofthe enteric coating are especially important for a tableted multipleunit dosage form, i.e. the individually enteric coated units mustwithstand the compression into a tableted multiple unit dosage formwithout any significant effect on the acid resistance. Suitableplasticizers are for instance, but not restricted to, triacetin, citricacid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol,polyethylene glycols, polysorbates or other plasticizers.

[0037] The preparation of the core material containing the proton pumpinhibitor and alkaline reacting compound(s) is described more in detailbelow. The individually enteric coated cores can be constitutedaccording to different principles.

[0038] The active substance, the proton pump inhibitor, used as aracemate or one of its single enantiomers or an alkaline salt of saidcompound or one of its single enantiomers, mixed with the alkalinereacting compound(s) is applied on seeds and are used for furtherprocessing.

[0039] The seeds, which are to be layered with the active substances,can be water insoluble seeds comprising different oxides, celluloses,organic polymers and other materials, alone or in mixtures or watersoluble seeds comprising different inorganic salts, sugars, non-pareilsand other materials, alone or in mixtures. Further, the seeds maycomprise active substance in the form of crystals, agglomerates,compacts etc. The size of the seeds is not essential for the presentinvention but may vary between approximately 0.1 and 2 mm. The seedslayered with active substance are produced either by powder orsolutior'suspension layering using for instance granulating or spraycoating/layering equipment.

[0040] Before the seeds are layered, the active substance is mixed withalkaline reacting compound(s) and further components to obtain preferredhandling and processing properties and suitable concentration of theactive substance. Pharmaceutical constituents such as fillers, binders,lubricants, disintegrating agents, surfactants and otherpharmaceutically acceptable additives, can be used. Binders are forexample celluloses such as hydroxypropyl methylcellulose, hydroxypropylcellulose and carboxymethylcellulose sodium, polyvinylpyrrolidone,sugars, starches and other pharmaceutically acceptable substances withcohesive properties. Suitable surfactants are found in the groups ofpharmaceutically acceptable non-ionic or ionic surfactants such as a forinstance sodium lauryl sulfate or polysorbates.

[0041] Alternatively, the active substance mixed with alkalinecompound(s) and further mixed with suitable constituents can beformulated into tablets or individual cores. Said tablets or cores maybe produced by compression/extrusion/spheronization or balling utilizingdifferent processing equipments. The manufactured tablets or cores canfurther be layered with additional ingredients comprising activesubstance and alkaline reacting compound(s) and/or be used for furtherprocessing.

[0042] The active substance may optionally be mixed with alkalinepharmaceutically acceptable substance (or substances) for furtherstabilisation. Such substances can be chosen among, but are notrestricted to, substances such as for instance the above mentionedalkaline reacting compounds or other alkaline reacting substances knownby the skilled person in the art to be useful as stabilizers for acidicsusceptable substances.

[0043] Alternatively, the aforementioned alkaline reacting core materialcan be prepared by the use of spray drying or spray congealingtechnique.

[0044] The prepared alkaline reacting core material in the form oftablets or pellets are spray coated with an aqueous enteric coatingpolymer dispersion/solution. The process parameters such as inlet airtemperature, air flow, atomizer air flow and spraying rate are adjustedwith respect to the equipment used for the process as well as thespecific enteric coating polymer(s). The inlet air temperature must notbe such that the enteric coating polymer(s) will block in the sprayingnozzles.

[0045] The invention is described more in detail by the followingexamples, which are not intended to limit the scope of the invention.

EXAMPLE 1

[0046] Tablets containing lansoprazole and arginine are producedaccording to the following procedure. Firstly, dry ingredients arethoroughly mixed and then granulated with a solution in a laboratorymixer. The dried granules are mixed with lubricants etc. in a finalmixing step. Concentration Dry ingredients for granulation (mmol/g dryingredients in (for approx. 4000 tablets) the alkaline tablet core)Lansoprazole 40.4 g L-arginine (passing 120 mesh) 365.4 g 4.2Microcrystalline cellulose 38.5 g Granulating solution Distilled water173 g Corn starch 7.7 g

[0047] The solution is poured over the premixed powder mass duringmixing. The wet granules are dried on a tray in a drying cabinet. Thedried granules are milled to pass a 1.0 mm sieve. The granules are mixedwith Talc 3.1 g Sodium dodecyl sulphate 20.8 g Microcrystallinecellulose 19.2 g Magnesium stearate 5.0 g

[0048] in a laboratory mixer, and then compressed into tablets having asize of 7 mm Ø and a weight of approximately 125 mg. The obtainedtablets have a content of lansoprazole of 10 mg per tablet.

[0049] Obtained tablets are spray coated with the enteric coatingdispersion defined below, in a Wurster equipped fluidized bed. Entericcoating dispersion Water 80.0 g Triethylcitrate 1.3 g Na-laurylsulphate0.2 g Hydroxypropylmethylcellulose acetate succinate LF 6.3 g Talc 1.9 g

[0050] This single coating step resulted in tablets having two polymericlayers with different characteristics. The inner layer is not soluble inacetone, as the outer layer, but soluble in water. FIG. 1, obtained withconfocal laser scanning microscopy (CLSM) shows a cross-section of thetablet where the separating layer is easily detected as a layer havingan intense fluorescence.

[0051] The separating layer is spontaneously formed in situ during theprocess, as a salt between the alkaline reacting compound and theenteric coating polymer.

EXAMPLE 2

[0052] Core material containing the magnesium salt of (−)-omeprazole andthe alkaline reacting compound trometamine (=tris-buffer) is prepared byextrusion and spheronization.

[0053] The powder mass is mixed in a laboratory mixer and then water isadded. Concentration (mmol/g dry ingredients in Powder mixture thealkaline core material) Magnesium salt of (−)- 400 g omeprazoleMicrocrystalline cellulose 300 g Trometamine 1000 g 4.1 PVP-XL 100 gMannitol pwd 195 g Hydroxypropyl methylcellulose 5 g 6 cps Water q.s.

[0054] The powder mixture is mixed with the water and the wet mass ismixed to obtain a suitable consistency of the mass.

[0055] Extrusion is performed with an extruder fitted with 1.0 mmscreen. The extrudate is formed into pellets on a spheronizer and driedin a fluidized bed drier.

[0056] 200 g of the obtained pellets are spray coated with the entericcoating dispersion described below, in a Wurster equipped fluidized bed.Enteric coating dispersion Water 93.9 g Polyethylene glycol 400 4.6 gEudragit ™ L30D-55 151.5 g

[0057] This single coating step resulted in pellets having two polymericlayers with different characteristics. The inner layer is not soluble inacetone as the outer layer, but soluble in water. The separating layeris spontaneously formed in situ during the process, as a salt betweenthe alkaline reacting compound and the enteric coating polymer.

[0058] Enteric coated pellets having a separating layer are obtained.These pellets may be filled in capsules or sachets for oraladministration.

EXAMPLE 3

[0059] Core material containing omeprazole and N-methyl-D-glucamine(=meglumine) is prepared by extrusion and spheronization of the belowdescribed composition using the same procedure as in Example 2;Concentration (mmol/g dry ingredients in Powder mixture the alkalinecore material) Omeprazole 100.0 g Microcrystalline cellulose 50.0 gMeglumine 500.0 g 2.6 Mannitol pwd 297.0 g Sodium starch glycolate 48.0g Sodium laurylsulphate 5.0 g Water q.s.

[0060] Obtained dried pellets/cores are spray coated with the entericcoating dispersion described below, in a Wurster equipped fluidized bed.Enteric coating dispersion Water 93.9 g Polyethylene glycol 400 4.6 gEudragit ™ L30D-55 151.5 g

[0061] This single coating step resulted in tablets having two polymericlayers with different characteristics. The inner layer is not soluble inacetone, as the outer one, but soluble in water. The separating layer isspontaneously formed in situ during the process, as a salt between thealkaline reacting compound and the enteric coating polymer.

[0062] The obtained pellets having a separating layer and an entericcoating layer, are suitable for filling into hard gelatine capsules orsachets for oral administration.

EXAMPLE 4

[0063] Core material containing magnesium salt of omeprazole andN-methyl-D-glucamine (meglumine ) is prepared by layer coating in aWurster equipped fluidized bed on sugar seeds. For this operation thefollowing materials are used; Concentration (mmol/g dry ingredients inSubstance Amount the alkali containing layer) Water purified 102 gEthanol 99% (w/v) 102 g HPMC 6 cps 2 g N-methyl-D-glucamine 3.3 g 0.37Magnesium salt of omeprazole 40 g Non Pareille 500 g

[0064] First the water and ethanol were mixed whereafter the HPMC wasdissolved in the obtained solution. N-methyl-D-glucamine and magnesiumsalt of omeprazole were dissolved/suspended in the solution. The sugarcores (Non Pareille) were used as starting seeds for the formation ofcore material. A peristaltic pump was used to feed the sprayingsuspension, which was fed with a velocity of 3.9 g/min.

[0065] The Wurster apparatus was equipped with a 60 mm high insertiontube, having a diameter of 50 mm, positioned to leave a 10 mm slit belowit. A spraying nozzle having a 0.8 mm opening was used. The atomizingair flow was 2.3 Nm³/h and air pressure used was 1.9 bar. The inlet airtemperature was 50° C. and flow used 43 m³/h.

[0066] After the core formation step, 100 grams of the obtained corematerial was film-coated by spraying with an enteric coating dispersionas described below, using the same equipment as in the core formationstep. Enteric coating dispersion Water purified 183 g Triethyl citrate2.9 g Sodium laurylsulphate 0.4 g Hydroxypropyl methylcellulose 14.4 gacetate succinate LF Talc 4.3 g

[0067] First the triethyl citrate was dissolved in the water, andthereafter the sodium laurylsulphate was added. Thehydroxypropylmethylcellulose acetate succinate was dispersed in thesolution, and then the talc was added. The dispersion was fed with arate of 3.8 g/min.

[0068] Inlet air temperature used was 42° C. and flow was set to 40Nm³/h. Atomizing air flow used was 2.1 Nm³/h , obtained with a pressureof 1.7 bar.

[0069] After finalizing the spraying, the inlet air temperature is risedto 60° C. and the product is kept at this temperature for appr. 5minutes.

[0070] This single film-coating step resulted in cores having twopolymeric coating layers with different characteristics. The inner layeris not soluble in acetone, as the outer layer, but soluble in water.Using confocal laser scanning microscopy to study a cross-section of thecores from this example, the presence of an inner layer was confirmed.

[0071] The separating layer is spontaneously formed in situ during theprocess, as a salt between the alkaline reacting compound and theenteric coating polymer.

EXAMPLE 5

[0072] A rotogranulator was used to produce spherical core unitscontaining pantoprazole. As starting material inert sugar seeds(Non-Pareille) with an average size between 0.6 to 0.71 mm _527 wasused. The sugar seeds were coating layered with the powder mixturedescribed below, by spraying a 5% solution of HPMC 6 cps in water.

[0073] The obtained core material containing pantoprazole was dried at40° C. for 16 hours in vacuum and then sieved to give granules between0.6 mm to 1.25 mm Ø. Starting material Non-Pareille 110 parts by weightConcentration (mmol/g dry ingredients in Powder mixture Amount thealkali containing layer) Pantoprazole 29.3 parts by weight L-Lysine 22.0″ 0.88 Sucrose 36.7 ″ Corn starch 42.5 ″ Microcrystalline 36.7″cellulose Solution Hydroxypropyl 2.9 ″ methylcellulose Water (58.7 ″)

[0074] 250 g of the core material produced in this way was spray coatedwith an enteric coating dispersion in a Wurster equipped fluidized bedapparatus. The dispersion was made by adding the mentioned ingredientsin stated order, while stirring. Dispersion Water 626.8 gTriethylcitrate 9.8 g Sodium-laurylsulphate 1.5 gHydroxypropylmethylcellulose 49.2 g acetate succinate LF Talc 14.8 g

[0075] Enteric coated pellets having a water soluble separating layerwere obtained. These pellets may be filled in capsules or sachets fororal administration.

EXAMPLE 6

[0076] Omeprazole tablets, 6 mm in diameter containing 20 mg ofomeprazole were prepared by mixing and granulating dry powderingredients with water in a Kenwood mixer. For this operation thefollowing materials are used; Concentration (mmol/g dry ingredients inthe alkaline Substance Amount tablet core) Omeprazole 40.0 g Mannitolpwd 68.0 g Microcrystalline cellulose 35.0 g Polyvinylpyrrolidonecross-linked 30.0 g Hydroxypropylcellulose low-substituted 20.0 gL-arginine 5.3 g 0.14 Sodium laurylsulphate 2.0 g Water purified q.s.approx 50 g Sodium stearylfumarate (SSF) 1.0 g

[0077] The dry powders except for SSF were mixed to homogeneity. Thismixture was moistened with the water and the wet mass dried on a tray ina drying oven. The obtained granules were milled to pass a screen with0.8 mm apertures. Then the lubricant SSF was mixed with the granulesusing the same Kenwood mixer as before.

[0078] Cores having an average weight of 101 mg were compressed on atableting machine equipped with 6 mm diameter punches.

[0079] After the core formation step, 50 grams of the obtained coreswere film-coated by spraying an aqueous enteric coating dispersion asdescribed below, using a Wurster equipped fluidized bed. Enteric coatingdispersion Substance Amount Water purified 183 g Triethyl citrate 2.9 gSodium laurylsulphate 0.4 g Hydroxypropylmethylcellulose 14.4 g acetatesuccinate LF Talc 4.3 g

[0080] This single film-coating step resulted in cores having twopolymeric coating layers with different characteristics. The inner layeris not soluble in acetone, as the outer layer, but soluble in water.

[0081] The separating layer is spontaneously formed in situ during theprocess, as a salt between the alkaline reacting compound and theenteric coating polymer.

EXAMPLE 7

[0082] Tablets, 7 mm in diameter containing omeprazole anddisodiumhydrogenphosphate was prepared by mixing and granulating drypowder ingredients with a water solution containing sodiumlaurylsulphate, in a Kenwood mixer. For this operation the followingmaterials are used: Concentration (mmol/g dry ingredients in SubstanceAmount the alkaline tablet core) Omeprazole 80.0 g Mannitol pwd 88 gMicrocrystalline cellulose 132 g L-HPC 53 g Disodiumhydrogenphosphate104 g 1.12 dihydrate Granulation liquid Water purified 80 g Sodiumlaurylsulphate 3 g Water purified q.s. Final mixing Sodiumstearylfumarate (SSF) 10 g Polyvinylpyrrolidone crosslinked 50 g

[0083] The dry powders except for SSF were mixed to homogenity. Thismixture was moistened first with the granulation liquid and then withwater until satisfactory consistency of the mass. The wet mass was driedon a tray in a drying oven. The obtained granules were milled to pass ascreen with 0.8 mm apertures and then the lubricant SSF and thedisintegrating agent polyvinylpyrrolidone crosslinked were mixed withthe obtained granules using the same Kenwood mixer as before.

[0084] Cores having an average weight of 130 mg were compressed on atableting machine equipped with 7 mm diameter punches.

[0085] After the core formation step, 50 grams of the obtained coreswere film-coated by spraying with an aqueous enteric coating dispersionas described below, using a Wurster equipped fluidized bed. Entericcoating dispersion Water purified 183 g Triethyl citrate 2.9 g Sodiumlaurylsulphate 0.4 g Hydroxypropyl methylcellulose 14.4 g acetatesuccinate LF Talc 4.3 g

[0086] This single film-coating step resulted in cores having twopolymeric coating layers with different characteristics. The inner layeris not soluble in acetone, as the outer layer, but soluble in water. Theseparating layer is spontaneously formed in situ during the process, asa salt between the inorganic alkaline reacting compound and the entericcoating polymer.

REFERENCE EXAMPLES 1 AND 2

[0087] Placebo tablets, 6 mm in diameter was prepared by mixing andgranulating dry powder ingredients with water in a Kenwood mixer. Forthis operation the following materials are used; Concentration (mmol/gdry ingredients Amount containing layer) Substance Ref. Ex. 1 Ref. Ex. 2Ref Ex. 1 Ref. Ex. 2 Mannitol pwd 161.5 g 141.3 g Microcrystalline 38.5g 38.5 g cellulose Na₂HPO₄ × 2H₂O — 20.2 g — 0.56 Water purified q.s. 45g 45 g approx Sodium stearylfumarate 1.0 g 1.0 g (SSF)

[0088] The dry powders except for SSF were mixed to homogeneity. Thismixture was moistened with the water and the wet mass dried on a tray ina drying oven. The obtained granules were milled to pass a screen with0.8 mm apertures. Then the lubricant SSF was mixed with the granulesusing the same Kenwood mixer as before.

[0089] Cores having an average weight of 93-94 mg were compressed on atableting machine equipped with 6 mm diameter punches.

[0090] After the core formation step, 50 grams of each kind of theobtained cores were (separately) film-coated by spraying an aqueousenteric coating dispersion according to below, using a Wurster equippedfluidized bed. Enteric coating dispersion Substance Amount Waterpurified 183 g Triethyl citrate 2.9 g Sodium laurylsulphate 0.4 gHydroxypropylmethylcellulose 14.4 g acetate succinate LF Talc 4.3 g

[0091] These reference examples show that presence of the alkalinematerial in the core material composition is necessary for the formationof an in situ formed spontaneously developed separating layer.

[0092] For Reference Ex. 1, this single film-coating step resulted incores having only one coating layer, being soluble in acetone. Noseparating layer was spontaneously formed.

[0093] For Reference Ex. 2, this single film-coating step resulted incores having two polymeric coating layers with differentcharacteristics. The inner layer is not soluble in acetone, as the outerlayer, but soluble in water. The separating layer is spontaneouslyformed in situ during the process, as a salt between the alkalinereacting compound and the enteric coating polymer.

[0094] By using confocal laser scanning microscopy to study across-section of the cores from the Reference example 2, the presence ofan inner layer was confirmed. In contrast, examining a cross-section ofa core from Reference example 1, no inner layer was seen.

[0095] The best mode to practice the invention is by the formulationsdescribed in Examples 1 and 2.

[0096] The different active substances, i.e. proton pump inhibitors, areprepared according to information disclosed in the Patent specificationsmentioned in page 6 of this specification.

1. An oral pharmaceutical dosage form comprising a core material thatcontains a proton pump inhibitor, one or more alkaline reactingcompound(s) and optionally pharmaceutically s acceptable excipientshaving a water soluble separating layer and an enteric coating layercharacterized in that the core material is alkaline reacting and thatthe separating layer is being formed in situ during the enteric coatingas a water soluble salt between the enteric coating layer polymer(s) andthe alkaline reacting compound(s).
 2. A dosage form according to claim1, wherein the alkaline reacting compounds are selected from the groupof alkaline organic substances, hydroxides of alkali metals or one oftheir alkaline salts of phosphoric acid, carbonic acid or silicic acid,or an alkaline ammonium salt.
 3. A dosage form according to claim 2,wherein the alkaline reacting substance is a hydroxide of an alkalimetal or an alkaline salt of phosphoric acid, carbonic acid or silicicacid, or an alkaline ammonium salt.
 4. A dosage form according to claim2, wherein the alkaline reacting compound is an alkaline organicsubstance, e.g. an amino acid or a salt thereof, an alkaline amine or aderivative thereof, or an alkaline salt of a weak organic acid.
 5. Adosage form according to claim 2, wherein the alkaline organic substanceis an amino acid, e.g. lysine, arginine, ornitine or histidine, or analkaline amine or a derivative thereof, e.g. N-methyl-D-glucamine ortrometamine.
 6. A dosage form according to claim 1, wherein the alkalinereacting compounds are present in a concentration of more than 0.1mmol/g dry ingredients in the alkaline part of the core material.
 7. Adosage form according to claim 1, wherein the enteric coating polymer(s)is/are hydroxypropyl cellulose derivative(s), e.g.hydroxypropylmethylcellulose acetate succinate.
 8. A dosage formaccording to claim 1, wherein the enteric coating polymer iscopolymerized methacrylic acid/methacrylic acid methyl esters.
 9. Adosage form according to claim 1, wherein the proton pump inhibitor is acompound of the general formula I or a pharmaceutically acceptable saltthereof or a pure enantiomer thereof in neutral form or in the form ofan alkaline salt

wherein N in the benzimidazole moiety means that one of the carbonatorssubstituted by R₆-R₉ optionally may be exchanged for a nitrogen atomwithout any substituents; R₁, R₂ and R₃ are the same or different andselected from hydrogen, alkyl alkoxy optionally substituted by fluorine,alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen,phenyl and phenylalkoxy; R₄ and R₅ are the same or different andselected from hydrogen, alkyl and aralkyl; R′₆ is hydrogen, halogen,trifluoromethyl, alkyl and alkoxy; R₆-R₉ are the same or different andselected from hydrogen, alkyl alkoxy, halogen, halo-alkoxy,alkylcarbonyl, alkoxycarbonyl, oxazolyl trifluoroalkyl or adjacentgroups R₆-R₉ form ring structures which may be further substituted; R₁₀hydrogen or forms an alkylene chain together with R₃ and R₁₁ and R₁₂ arethe same or different and selected from hydrogen, halogen or alkyl andalkyl groups, alkoxy groups and moities thereof may be branched andstraight C₁-C₉-chains or comprise cyclic alkyl groups, for examplecycloalkylalkyl.
 10. A dosage form according to claim 1, wherein theproton pump inhibitor is omeprazole or an alkaline salt thereof.
 11. Adosage form according to claim 1, wherein the proton pump inhibitor is apure enantiomer of omeprazole or an alkaline salt thereof.
 12. A dosageform according to claim 1, wherein the proton pump inhibitor islansoprazole, one of its pure enantiomers or a pharmaceuticallyacceptable salt thereof.
 13. A dosage form according to claim 1, whereinthe proton pump inhibitor is pantoprazole, one of its pure enantiomersor a pharmaceutically acceptable salt thereof.
 14. A dosage formaccording to claim 1, wherein the alkaline reacting core material isindividual pellets intended for a capsule formulation or a tabletedmultiple unit dosage form.
 15. A dosage form according to claim 1,wherein the alkaline reacting core material is a tablet.
 16. A dosageform according to claim 1, wherein individually enteric coated pelletsare compressed into a tableted multiple unit dosage form.
 17. A processfor the preparation of an oral, enteric coated pharmaceutical dosageform comprising a core material that contains a proton pump inhibitor,one or more alkaline reacting compounds and optionally pharmaceuticallyacceptable excipients having a water soluble separating layer and anenteric coating layer characterized in that an alkaline reacting corematerial is prepared and coated with an enteric coating polymer whereina separating layer between the core material and the enteric coatinglayer is formed in situ by a reaction between the enteric coatingpolymer(s) and the alkaline reacting compound(s) in the core materialduring the application of the enteric coating onto the alkaline reactingcore material.
 18. An oral, pharmaceutical dosage form comprising aproton pump inhibitor as defined in any of claims 1-16 for use ininhibiting gastric acid secretion in mammals and man.
 19. A method forinhibiting gastric acid secretion in mammals and man by administering toa host in need thereof a dosage form comprising a therapeuticallyeffective dose of a proton pump inhibitor as defined in any of claims1-16.
 20. Use of an oral pharmaceutical dosage form defined in any ofclaims 1-16 for the manufacture of a medicament useful in the treatmentof gastric acid related diseases.